Enzyme activities of leukemic cells and biochemical changes induced by deoxycoformycin in vitro—Lack of correlation with clinical response

1989 ◽  
Vol 13 (4) ◽  
pp. 269-278 ◽  
Author(s):  
Anthony D. Ho ◽  
Kanagasabai Ganeshaguru ◽  
Wolfgang Knauf ◽  
Günther Dietz ◽  
Irmtraut Trede ◽  
...  
Keyword(s):  
Clinical Response ◽  
Enzyme Activities ◽  
Biochemical Changes ◽  
Leukemic Cells

scholarly journals Clinical response to deoxycoformycin in chronic lymphoid neoplasms and biochemical changes in circulating malignant cells in vivo

Blood ◽  
1988 ◽  
Vol 72 (6) ◽  
pp. 1884-1890 ◽  
Author(s):  
AD Ho ◽  
K Ganeshaguru ◽  
WU Knauf ◽  
G Dietz ◽  
I Trede ◽  
...  
Keyword(s):  
Clinical Response ◽  
Dna Strand Breaks ◽  
Biochemical Changes ◽  
Leukemic Cells ◽  
Malignant Cells ◽  
Dna Breaks ◽  
Strand Breaks ◽  
Lymphoid Neoplasms ◽  
Dna Strand

Abstract Deoxycoformycin (DCF), an adenosine deaminase (ADA) inhibitor, has been shown to be active in lymphoid neoplasms. The mechanism of cytotoxicity might involve accumulation of deoxyadenosine triphosphate (dATP), depletion of the nicotinamide adenine dinucleotide (NAD) and ATP pool, induction of double-stranded DNA strand breaks, or inhibition of S- adenosyl homocysteine hydrolase (SAH-hydrolase). We have investigated the biochemical changes in the circulating malignant cells of patients with chronic leukemia/lymphoma who were treated with DCF (4 mg/m2 weekly). Blood samples were taken from 17 patients with 60% or more circulating leukemic cells before, 4, 24, and 48 hours and five days after the first administration of DCF. Leukemic cells were separated and studied for changes in ADA, dATP, ATP, NAD, and SAH-hydrolase levels and DNA strand breaks and the data analyzed according to clinical response. Inhibition of ADA activity was found in all except one patient at 4 to 24 hours after the first administration of DCF. dATP started to accumulate at four hours, reached a maximum level between 24 and 48 hours, and returned to base values on the fifth day. Intracellular ATP and NAD levels were transiently reduced in some of the patients. However, no correlation between these changes and a clinical response could be found. DNA strand breaks could be studied in 13 patients. A significant increase in DNA breaks at 24 to 48 hours was found in six of the seven responders but only in one of the six nonresponders. At 24 hours, SAH-hydrolase levels were reduced in all seven responders studied, but only in two of the seven nonresponders. The difference in inhibition of SAH-hydrolase was statistically significant (P = .0023). These results suggest that DNA strand breaks and inhibition of SAH-hydrolase correlate with clinical response.

Pharmacokinetic and Pharmacodynamic Effects of PEG-Asparaginase in Newly Diagnosed Childhood Acute Lymphoblastic Leukemia: Results from a Single Agent Window Study.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 860-860
Author(s):  
Inge M. Appel ◽  
Karin M. Kazemier ◽  
Anjo J.P. Veerman ◽  
Elisabeth van Wering ◽  
Monique L. Den Boer ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Clinical Response ◽  
Lymphoblastic Leukemia ◽  
Single Agent ◽  
Hazard Ratio ◽  
Leukemic Cells ◽  
Newly Diagnosed ◽  
Pharmacodynamic Effects

Abstract L-Asparaginase is an effective drug for treatment of children with acute lymphoblastic leukemia. The effectiveness is generally thought to result from a rapid depletion of asparagine in serum and cells. Several studies have shown that in vitro resistance to this drug is an independent prognostic factor in ALL. We investigated the clinical response of one in vivo dose of 1000 IU/m2 PEG-Asparaginase and its pharmacokinetic and pharmacodynamic effects in children with newly diagnosed ALL before the start of combination chemotherapy. 57 children (36M / 21F) were enrolled in the study: 2 pro B-ALL, 38 common/ pre B-ALL and 17 T-ALL. Genotyping of precursor B-ALL revealed 11 hyperdiploid, 8 TELAML1 positive, 2 BCRABL positive, no MLL rearrangement, 8 normal, 11 others. The clinical response to PEG-Asparaginase on day 0 (5 days after the PEG-Asparaginase infusion) was defined as good when the number of leukemic cells of peripheral blood was < 1 × 109/L, as intermediate when leukemic cells were 1-10 × 109/L, and as poor when leukemic cells were > 10 × 109/L. The in vivo window response was significantly related to immunophenotype and genotype: 26/38 common / pre B-ALL cases, especially those with hyperdiploidy and TELAML1 rearrangement, demonstrated a good clinical response compared to 8/17 T-ALL (p=0.01). Both BCRABL positive ALL cases showed a poor response (p=0.04). A poor in vivo clinical window response was related to in vitro resistance to L-Asparaginase (p=0.02) and both in vitro as well as in vivo response were prognostic factors for long-term event-free survival (Hazard ratio 6.4; p=0.004, and Hazard ratio 3.7; p=0.01, respectively). The L-Asparaginase activity in the serum was >100 IU/L for at least 15 days. The asparagine levels remained below the detection limit of 0.2 mM for at least 26 days with a concomitant rise in serum aspartate and glutamate. These findings confirm that PEG-Asparaginase will yield its pharmacodynamic effects for 2-4 weeks. After administration of one in vivo dose of 1000 IU/m2 PEG-Asparaginase no changes in apoptotic parameters or changes in intracellular levels of twenty amino acids in leukemic cells could be measured, in contradiction to the changes found after in vitro exposure. This may be explained by the rapid removal of apoptotic cells from the circulation in vivo. Otherwise it is possible that in vivo mesenchymal cells from the bone marrow supply leukemic blasts with asparagine in response to treatment with L-Asparaginase. Conclusion: The clinical response to one dose of 1000 IU/m2 PEG-Asparaginase intravenously is related to phenotype and genotype and predicts outcome. These results suggest that children with ALL with a poor clinical response to PEG-Asparaginase might benefit from a more intensive antileukemic therapy.

scholarly journals Clinical response to deoxycoformycin in chronic lymphoid neoplasms and biochemical changes in circulating malignant cells in vivo

Blood ◽  
1988 ◽  
Vol 72 (6) ◽  
pp. 1884-1890
Author(s):  
AD Ho ◽  
K Ganeshaguru ◽  
WU Knauf ◽  
G Dietz ◽  
I Trede ◽  
...  
Keyword(s):  
Clinical Response ◽  
Dna Strand Breaks ◽  
Biochemical Changes ◽  
Leukemic Cells ◽  
Malignant Cells ◽  
Dna Breaks ◽  
Strand Breaks ◽  
Lymphoid Neoplasms ◽  
Dna Strand

Deoxycoformycin (DCF), an adenosine deaminase (ADA) inhibitor, has been shown to be active in lymphoid neoplasms. The mechanism of cytotoxicity might involve accumulation of deoxyadenosine triphosphate (dATP), depletion of the nicotinamide adenine dinucleotide (NAD) and ATP pool, induction of double-stranded DNA strand breaks, or inhibition of S- adenosyl homocysteine hydrolase (SAH-hydrolase). We have investigated the biochemical changes in the circulating malignant cells of patients with chronic leukemia/lymphoma who were treated with DCF (4 mg/m2 weekly). Blood samples were taken from 17 patients with 60% or more circulating leukemic cells before, 4, 24, and 48 hours and five days after the first administration of DCF. Leukemic cells were separated and studied for changes in ADA, dATP, ATP, NAD, and SAH-hydrolase levels and DNA strand breaks and the data analyzed according to clinical response. Inhibition of ADA activity was found in all except one patient at 4 to 24 hours after the first administration of DCF. dATP started to accumulate at four hours, reached a maximum level between 24 and 48 hours, and returned to base values on the fifth day. Intracellular ATP and NAD levels were transiently reduced in some of the patients. However, no correlation between these changes and a clinical response could be found. DNA strand breaks could be studied in 13 patients. A significant increase in DNA breaks at 24 to 48 hours was found in six of the seven responders but only in one of the six nonresponders. At 24 hours, SAH-hydrolase levels were reduced in all seven responders studied, but only in two of the seven nonresponders. The difference in inhibition of SAH-hydrolase was statistically significant (P = .0023). These results suggest that DNA strand breaks and inhibition of SAH-hydrolase correlate with clinical response.

Clinical Trial of Paricalcitol in Myelodysplastic Syndrome.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4720-4720
Author(s):  
H. Phillip Koeffler ◽  
James O’Kelly ◽  
Noune Aslanian ◽  
Keyword(s):  
Clinical Trial ◽  
Myelodysplastic Syndrome ◽  
Clinical Response ◽  
Vitamin D3 ◽  
Single Agent ◽  
White Blood Cells ◽  
The Elderly ◽  
Leukemic Cells

Abstract Myelodysplastic syndrome is often a pernicious disorder associated with pancytopenia in the elderly. Therapeutic approaches need to balance their toxicities versus the side-effects of the disease. 1,25(OH)2-vitamin-D3 inhibits proliferation and induces differentiation of leukemic cells in vitro. Small clinical trials have shown slight efficacy in MDS. Hypercalcemia prevents the administration of doses of this seco-steroid, which have been shown to be effective in vitro. This has provided a stimulus to identify vitamin D analogs that have anti-leukemic activity with minimal hypercalcemic effects. Paricalcitol (19-nor-1,25(OH)2D2, Zemplar) has been approved by the FDA for the treatment of secondary hyperparathyroidism; the drug is unique because it has little hypercalcemic potential; but in vitro, it has strong antileukemic effects. We conducted a clinical trial of oral paricalcitol to twelve MDS patients whose disease varied between an IPSS of low to high. Therapy began at 8 μg per day and increased at two week intervals until serum calcium was slightly above normal level; at which point, dose was decreased by 4-8 μg qd. The amount of paricalcitol taken varied between 8 μg qod to 54 μg qd (average 16 μg qd). We confirmed that the drug was having biologic activity in vivo by examining a target of the activated vitamin D3 receptor, 1,25-(OH)2-vitamin-D3-24(OH)ase mRNA. Each patient had prominent induction of this transcript in his or her white blood cells. Furthermore, in selected patients serum paricalcitol was measured and confirmed to be prominently present. The drug was well tolerated in all patients. Two of the 12 patients showed a clinical response. One patient’s platelet counts rose from 50,000 to 120,000/ul blood over 5 weeks; however, the patient succumbed to a fatal fungal infection. The second patient responded by a decrease in RBC transfusions associated with a rise in his hemoglobin, which lasted for about 5 months. Eventually, his hemoglobin began to fall, and erythropoietin therapy was substituted for paricalcitol. In summary, high doses of paricalcitol were well tolerated in all patients. Two patients had a partial clinical response. In general, paricalcitol given as a single agent to individuals with MDS is not therapeutically very efficacious; further trials should examine it in combination with other approaches.

scholarly journals Colony formation in vitro by leukemic cells in acute lymphoblastic leukemia (ALL)

Blood ◽  
1978 ◽  
Vol 52 (4) ◽  
pp. 712-718 ◽  
Author(s):  
SD Smith ◽  
EM Uyeki ◽  
JT Lowman
Keyword(s):  
Bone Marrow ◽  
Acute Lymphoblastic Leukemia ◽  
Bone Marrow Cells ◽  
Lymphoblastic Leukemia ◽  
Lymphoid Cells ◽  
Assay System ◽  
Leukemic Cells ◽  
Specific Cell ◽  
Specific Cell Surface

Abstract An assay system in vitro for the growth of malignant lymphoblastic colony-forming cells (CFC) was established. Growth of malignant myeloblastic CFC has been previously reported, but this is the first report of growth of malignant lymphoblastic CFC. Established assay systems in vitro have been very helpful in elucidating the control of growth and differentiation of both normal and malignant bone marrow cells. Lymphoblastic CFC were grown from the bone marrow aspirates of 20 children with acute lymphoblastic leukemia. Growth of these colonies was established on an agar assay system and maintained in the relative hypoxia (7% oxygen) of a Stulberg chamber. The criteria for malignancy of these colonies was based upon cellular cytochemical staining characteristics, the presence of specific cell surface markers, and the ability of these lymphoid cells to grow without the addition of a lymphoid mitogen. With this technique, specific nutritional requirements and drug sensitivities can be established in vitro, and these data may permit tailoring of individual antileukemic therapy.

scholarly journals Evidence for the interleukin-2 dependent expansion of leukemic cells in adult T cell leukemia

Blood ◽  
1987 ◽  
Vol 70 (5) ◽  
pp. 1407-1411 ◽  
Author(s):  
M Maeda ◽  
N Arima ◽  
Y Daitoku ◽  
M Kashihara ◽  
H Okamoto ◽  
...  
Keyword(s):  
T Cell ◽  
Receptor Gene ◽  
Interleukin 2 ◽  
Leukemic Cells ◽  
Type I ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
In Vitro Proliferation ◽  
Adult T Cell Leukemia

Abstract Interleukin 2 (IL-2) receptor/Tac antigen is abnormally expressed on cells of patients with adult T cell leukemia (ATL) caused by infection with human T lymphotropic virus type I (HTLV-I). Twenty-five patients with ATL were examined to determine whether their leukemic cells continued to show IL-2-dependent proliferation. In 21 patients, the in vitro proliferation of HTLV-I-infected nonleukemic T cell clones was found to be dependent on IL-2. However, clonality analysis based on T cell receptor gene rearrangement profiles and the site of HTLV-I provirus integration revealed IL-2-dependent growth in leukemic cells in four patients with ATL. These results provide evidence for the IL-2- dependent proliferation of leukemic cells in some ATL patients.

In vitro Inhibition of Pancreatic Enzyme Activities by Dietary Fiber

Digestion ◽  
1982 ◽  
Vol 24 (1) ◽  
pp. 54-59 ◽  
Author(s):  
G. Isaksson ◽  
I. Lundquist ◽  
I. Ihse
Keyword(s):  
Dietary Fiber ◽  
Enzyme Activities ◽  
Pancreatic Enzyme ◽  
In Vitro Inhibition

scholarly journals Efficacy of loading dose colistin versus carbapenems for treatment of extended spectrum beta lactamase producing Enterobacteriaceae

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Wasan Katip ◽  
Jukapun Yoodee ◽  
Suriyon Uitrakul ◽  
Peninnah Oberdorfer
Keyword(s):  
Clinical Response ◽  
Clinical Information ◽  
Resistant Bacteria ◽  
Loading Dose ◽  
Extended Spectrum Beta Lactamase ◽  
Clinical Utilization ◽  
The Difference ◽  
Infection Types ◽  
Intra Abdominal Infection

AbstractColistin provides in vitro activity against numerous ESBL-producing and carbapenem-resistant bacteria. However, clinical information with respect to its utilization in infection caused by ESBL producers is limited. The aim of this study was a comparison of mortality rates of loading dose (LD) colistin and carbapenems as definitive therapies in a cohort of patients with infections caused by ESBL-producing Escherichia coli and Klebsiella pneumoniae. A retrospective cohort study in 396 patients with ESBL-producing E.coli and K.pneumoniae infection at a university-affiliated hospital was conducted between 1 January 2005 and 30 June 2015 to compare outcomes of infected patients who received LD colistin (95 patients) with carbapenems (301 patients). The three primary outcomes were 30-day mortality, clinical response and microbiological response. The most common infection types were urinary tract infection (49.49%), followed by pneumonia (40.66%), bacteremia (13.64%), skin and soft tissue infections (4.80%) and intra-abdominal infection (3.03%). LD colistin group provided higher 30-day mortality when compared with carbapenems group (HR 7.97; 95% CI 3.68 to 17.25; P = 0.001). LD colistin was also independently associated with clinical failure (HR 4.30; 95% CI 1.93 to 9.57; P = 0.001) and bacteriological failure (HR 9.49; 95% CI 3.76 to 23.96; P = 0.001) when compared with those who received carbapenems. LD colistin treatment was associated with poorer outcomes, i.e. mortality rate, clinical response and microbiological response. Moreover, when adjusted confounding factors, LD colistin was still less effective than carbapenems. It should be noted that, however, the use of Vitek-2 to assess colistin susceptibility could provide inaccurate results. Also, the difference in baseline characteristics could still remain in retrospective study although compensation by hazard ratio adjustment was performed. Therefore, clinical utilization of LD colistin should be recommended as an alternative for treatment ESBL-producing Enterobacteriaceae only in the circumstances where carbapenems cannot be utilized, but this recommendation must be considered carefully.

scholarly journals Therapeutic effects of sesamolin on leukemia induced by WEHI-3B in model mice

2021 ◽  
Vol 64 (1) ◽  
Author(s):  
Senthil Nagarajan ◽  
Jae Kwon Lee
Keyword(s):  
Nk Cell ◽  
Neoplastic Cell ◽  
Positive Control ◽  
Cytolytic Activity ◽  
Leukemic Cells ◽  
Therapeutic Effects ◽  
Control Drug ◽  
Lysis Activity

AbstractSesamolin is one of the lignans derived from sesame oil. It has demonstrated significant antioxidant, anti-aging, and anti-mutagenic properties. It also reportedly augments natural killer (NK) cell lysis activity. We previously reported that sesamolin also exerts anticancer effects in vitro and induces enhanced NK cell cytolytic activity against tumor cells. Herein, we aimed to determine the mechanism by which sesamolin prevents and retards tumorigenesis in BALB/c mouse models of leukemia induced by murine (BALB/c) myelomonocytic leukemia WEHI-3B cells. Banded neutrophils, myeloblasts, and monocytic leukemic cells were more abundant in the leukemia model than in normal mice. Sesamolin decreased the number of leukemic cells by almost 60% in the leukemia model mice in vivo; additionally, sesamolin and the positive control drug, vinblastine, similarly hindered neoplastic cell proliferation. Spleen samples were ~ 4.5-fold heavier in leukemic mice than those obtained from normal mice, whereas spleen samples obtained from leukemic mice treated with sesamolin had a similar weight to those of normal mice. Moreover, sesamolin induced a twofold increase in the cytotoxic activity of leukemic mouse NK cells against WEHI-3B cells. These results indicated that sesamolin exerts anti-leukemic effects in vivo.

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